著者

原 修 中尾 一成 棚田 喜久 西尾 東 松原 淳 横川 文明 濱田 康正 塩入 孝之

出版者

天然有機化合物討論会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

no.32, pp.617-624, 1990-09-25

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Calyculins having high cytotoxicity were isolated from the marine sponge Discordermia calyx in the Gulf of Sagami. Calyculin A (1), the major cytotoxic constituent, has 15 chiral centers, a spiroketal bearing phosphate, an oxazole ring, and a nitrile conjugated with all (E)-tetraene. However, its absolute stereostructure has remained uncovered. Interestingly, calyculin A (1) exhibits antitumor activity against Ehrlich and P-388 leukemia in mice. Its unique complex structure as well as its intriguing biological activity led us to investigate the total synthesis of 1, which will determine the absolute configuration of 1 as well. Retrosynthetic analysis has revealed that 1 would be constructed from four fragments A, B, C, and D, shown in Chart 1. Fragments A and B could be prepared by stereoselective reduction of tetronic acid derivatives 11 and 24, respectively. Fragments C and D were prepared from amino acids utilizing the methodology developed by us earlier.

著者

林 恭子 濱田 康正 塩入 孝之

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.33, pp.109-115, 1991

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Dolastatin 10, a potent antineoplastic substance, was isolated from an Indian Ocean sea hare, Dolabella auricularia. The absolute stereostructure of dolastatin 10, four constituents of which are unusual amino acids, was unambiguously determined by its total synthesis to be 1. Since the reported synthesis lacks stereo-selectivity, we have developed a more efficient route to dolastatin 10, a medicinally interesting peptide. Z-(S)-Dolaphenine was prepared by the Hantzsch method using Z-L-Phe-NH_2 as a starting material. (2R, 3R, 4S)-Dolaproine was prepared from Boc-(S)-prolinal (5) and N-propionyloxazolidinone 4 by the Evans aldol methodology. The unexpected threo aldol adduct 7 was produced as the major product with a small amount of the expected erythro adduct 6 when di-n-butylboron triflate was used in excess (Table 1). Stereochemistries of these aldol adducts were determined on the basis of ^1H-NMR analyses of their corresponding cyclic derivatives 18. Further investigation about this reversal of selectivity was carried out with a variety of aldehydes including amino aldehydes under the above reaction conditions (Table 2). (3R, 4S, 5S)-Dolaisoleuine, an isostatine analogue, was prepared from Boc-L-isoleucine via the β-ketoester 22, and (S)-dolavaline was prepared from L-valine according to the literature. Assembling each constituent obtained above was efficiently carried out in a stepwise manner from the C-terminal. DEPC was mainly used for the coupling, and the attachment of Boc-L-valine with the tripeptide fragment was accomplished by use of Bop-Cl. Dolastatin 10 (1) thus synthesized was identical with the natural one in every respect.

著者

林 恭子 濱田 康正 塩入 孝之

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.33, pp.109-115, 1991

---

Dolastatin 10, a potent antineoplastic substance, was isolated from an Indian Ocean sea hare, Dolabella auricularia. The absolute stereostructure of dolastatin 10, four constituents of which are unusual amino acids, was unambiguously determined by its total synthesis to be 1. Since the reported synthesis lacks stereo-selectivity, we have developed a more efficient route to dolastatin 10, a medicinally interesting peptide. Z-(S)-Dolaphenine was prepared by the Hantzsch method using Z-L-Phe-NH_2 as a starting material. (2R, 3R, 4S)-Dolaproine was prepared from Boc-(S)-prolinal (5) and N-propionyloxazolidinone 4 by the Evans aldol methodology. The unexpected threo aldol adduct 7 was produced as the major product with a small amount of the expected erythro adduct 6 when di-n-butylboron triflate was used in excess (Table 1). Stereochemistries of these aldol adducts were determined on the basis of ^1H-NMR analyses of their corresponding cyclic derivatives 18. Further investigation about this reversal of selectivity was carried out with a variety of aldehydes including amino aldehydes under the above reaction conditions (Table 2). (3R, 4S, 5S)-Dolaisoleuine, an isostatine analogue, was prepared from Boc-L-isoleucine via the β-ketoester 22, and (S)-dolavaline was prepared from L-valine according to the literature. Assembling each constituent obtained above was efficiently carried out in a stepwise manner from the C-terminal. DEPC was mainly used for the coupling, and the attachment of Boc-L-valine with the tripeptide fragment was accomplished by use of Bop-Cl. Dolastatin 10 (1) thus synthesized was identical with the natural one in every respect.